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SUMMIT (PUMA-NER-5201) Basket TrialEGFR exon 18 lung cancer cohort update

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EGFR exon 18 mutations are rare in NSCLC adenocarcinomas: represents only 5% of all EGFR mutations detected in lung cancer

S.V. Sharma et al (2007) Nature Rev. Cancer. 7:169–181

EGFR Exon

EGFR mutations associated with drug resistance

EGFR mutations associated with drug sensitivity

EGFR exon 18 mutations

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EGFR exon 18 mutations are highly sensitive to neratinib (irreversible pan-HER TKIs) in vitro studies

Source: Kobayashi et al. Clin Cancer Res 2015;21:5305-5313.

Western blot analyses of transfected HEK293 cellsComparative TKI affects in EGFR exon 18+ cells

Neratinib

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EGFR exon 18 mutations are highly sensitive to neratinib in NSCLC patients from POC trial

EGFR G719X+

Phase 2 trial of neratinib in lung cancer

4 of 167 (2%) patients had EGFR exon 18 mutations (G719X)– One patient did not have measurable disease by central review

All patients with G719 mutations (n=4) had clinical benefit– 3 PRs – mPFS 52.7 weeks, [90% CI 25.6 - 57.0 weeks)– 1 SD lasting >40 weeks

Source: L. Sequist et al (2010) J. Clin. Oncol. 28:3076-3083..

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SUMMIT study design for EGFR exon 18 mutant lung cancer cohort

EGFR exon 18-positiveLung Cancer

Neratinib monotherapy(240 mg, oral daily)

Clinical Trials.gov Identifier NCT01953926.

Mandatory Loperamide prophylaxis: oral 4 mg TID days 1–14, 4 mg BID days 15–46; as needed PRN

Open label single arm cohort

Primary endpoint• Objective response rate at first post-baseline tumor

assessment (Week 8) (ORRWk8)

Secondary endpoints• ORR (confirmed by RECIST criteria)• Duration of response (DOR)• Clinical benefit rate (CBR)• Progression-free survival (PFS)• Safety• Biomarkers

Simon 2-stage design• If ≥1 response in first evaluable 7 patients, expand

cohort to Stage 2 (N=18)• If ≥4 responses in Stage 2, expand or breakout

Tumor assessments• RECIST v1.1 (primary criteria)• PET response criteria (RECIST non-evaluable)

Statistical methods• ORRfirst, ORR, CBR: associated 95% CI• Median PFS: Kaplan-Meier estimate with 95% CI• DOR

Study Endpoints and Trial Design Features

• Patients who are receiving any other anticancer agents• Symptomatic or unstable brain metastases• Women who are pregnant or breast-feeding• Known KRAS activating co-mutation

Key exclusion criteria

• Histologically confirmed lung cancers for which no curative therapy exists• Documented EGFR exon 18 mutation by local method (any CAP/CLIA-certified lab)• Prior treatment with EGFR or pan-HER TKI allowed (afatinib, dacomitinib, osimertinib etc)• ECOG status of 0 to 2• RECIST 1.1 disease only

Key inclusion criteria

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Patient characteristics Safety/Efficacy evaluable patients (n=11)Median (range), years

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EGFR exon 18 mutant lung cancer cohort receiving neratinib monotherapy: Efficacy summary

a Objective response rate (ORR) is defined as either a complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially metb Kaplan-Meier analysis in safety population. c Clinical benefit rate (CBR) is defined as confirmed CR or PR or stable disease (SD) for ≥16 weeks (within +/– 7-day visit window)DOR, duration of response; PFS, progression-free survival, * response ongoing

ParameterEfficacy evaluable patients

(n=11)TKI Pre-Treated

(n=10)

Objective response (confirmed),a nCRPRObjective response rate, % (95% CI)

404

36 (11–69)

404

40 (12–74)

Best overall response, nCRPRBest overall response rate, % (95% CI)

606

54 (23–83)

606

60 (26–88)

Median DOR,b months (95% CI)7.5 (4.0–NE)

(1.9*, 4.0, 7.5, 9.2*)7.5 (4.0–NE)

(1.9*, 4.0, 7.5, 9.2*)

Clinical benefit,c nCR or PRSD ≥16 weeksClinical benefit rate, % (95% CI)

844

73 (39–94)

844

80 (44–97)

Median PFS time to event, months (95% CI) 6.9b (2.1–NA) 9.1 (3.7–NA)

Data cut-off: 21-Aug-2020

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Mutation Category Best Response (RECIST v1.1)

Best Response

Data cut-off: 21-Aug-2020

EGFR exon 18 mutant lung cancer cohort receiving neratinib monotherapy: Treatment duration, best response and best change in tumor

Prior TKI

Prior TKI

0 8 16 24 32 40 48 56 64 72 80 88 96 104

5052 (E709_T710delinsD; FGFRamp)

1907 (G719C; S768I)

0155 (G719X; S768I)

1900 (G719A; E709A)

7904 (G719X; S768I)

1910 (G719C; S768I; T790M)

0712 (G719X; S768I)

0758 (G719X)

7902 (G719C; E709K)

0711 (G719X)

0902 (G719A)

Duration of Treatment (Weeks)

Duration of Treatment Partial Response (RECIST)

Ongoing Treatment Stable Diseases (RECIST)Progressive Disease (RECIST)

-100

-50

0

50

100

% C

hang

e in

Tum

or

Disease Progression (RECIST)G719XG719X + E709XG719X + S768I

E709_T710delinsD + EGFRamp

Stable Diseases (RECIST)Partial Response (RECIST)Ongoing Treatment

Prior TKI

G719C + S768I + T790M

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TEAESafety evaluable patients (n=11)

Any grade Grade ≥ 3

Diarrhea 5 (45.5) 0

Vomiting 4 (36.4) 0

Constipation 3 (27.3) 0

Nausea 3 (27.3) 0

Decreased appetite 3 (27.3) 1 (9.1)

Dizziness 2 (18.2) 0

Hypertension 2 (18.2) 0

Dry mouth 2 (18.2) 0

Fatigue 2 (18.2) 0

Data cut-off: 21-Aug-2020

EGFR exon 18 mutant lung cancer cohort receiving neratinib monotherapy: Most common treatment emergent adverse events >10%

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Lung EGFR (N)(N = 11)

Incidence of diarrhea, n (%)a

Any grade 5 (45.5)

Grade 1 4 (36.4)

Grade 2 1 (9.1)

Grade 3 0

Action taken with neratinib, n (%)

Leading to temporary hold 0

Leading to dose reduction 0

Leading to permanent discontinuation 0

Diarrhea leading to hospitalization, n (%) 0

Time to first diarrhea, median (range) in days 15 (3 – 253)

Time to first grade 2 diarrhea, median (range) in days 8 (8 – 8)

Duration of grade 2 diarrhea per episode, median (range) in days 2 (1 – 2)

Data cut-off: 21-Aug-2020

EGFR exon 18 mutant lung cancer cohort receiving neratinib monotherapy: Characteristics of treatment emergent diarrhea

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Historical response rates of afatinib in NSCLC patients with EGFR exon 18 mutations (G719X)

Yang et al. Journal of Thoracic Oncology (2020) 15(5): 803-815

TKI-naïve patients

TKI-pre-treated patients

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Milestones for neratinib in EGFR exon 18 mutant lung cancer cohort in SUMMIT study

§ The success criteria for the 1st stage and 2nd stage of the Simon’s 2-stage design has been met§ Enrollment in the 2nd stage is continuing up to a total of 30 patients

§ Anticipate presentation of additional data from SUMMIT in patients with EGFR exon 18 mutant lung cancer in H1 2021

§ Anticipate scheduling meeting with FDA to discuss potential accelerated approval strategy for patients with EGFR exon 18 mutant lung cancer who have been treated with a prior EGFR TKI in 2021